Injectable compositions

ABSTRACT

A stable injectable composition includes a non-aqueous parasitic agent in a therapeutically effect amount, chosen from the group of avermectin, ivermectin, doramectin, abamectin, milbemycin and moxidecting, and an antigen in combination with a liquid carrier that also acts as an adjuvant for use with warm-blooded animals and a method for treating parasitic diseases and preventing bacterial and viral diseases in warm-blooded animals.

TECHNICAL FIELD OF THE INVENTION

This invention relates to novel compositions of macrolide avermectin andmilbemycin endecticides with an immunising agent and in particular itrelates to a stable injectable composition for use with warm-bloodedanimals, in particular ruminants.

The use of a combination of an parasitic agent and immunising agent as asingle injectable formulation offers advantages both in time and costsaving to the farmer.

BACKGROUND

New Zealand Patent Nos. 191413 and 193807 of ICI Tasman Limited disclosewater based formulations of D, L-tetramisole and clostridial vaccine inthe treatment of helminthiasis and clostridial diseases in warm-bloodedanimals. Both D, L-tetramisole and the clostridial vaccine are watersoluble hence a combination of the two is straight forward. What wassurprising was that the clostridial vaccine remained effective at a pHlower than 6.0 and that the combination improved the immune response inruminants, though not in other animals.

These aqueous formulations commonly used an adjuvant such as alum oralum hydroxide to enhance the effect of the antigen. Such adjuvants areusually included in the formulation as an aqueous suspensions. Thevaccines can then be readily mixed with water based anthelminticformulations.

Since the use of D, L-tetramisole and more particularly the L-isomerlevamisole, there have been a number of other potent antiparasiticmacrocyclic lactone compounds such as the avermectins, ivermectin,doramectin, abamectin, milbemycin, moxidectin used in the treatment ofdiseases in warm blooded animals. These later parasiticides areinsoluble in water which creates difficulties in formulating stableinjectable compositions. However, the compounds have the advantage thatthey are active against internal and external parasites in domesticanimals.

Formulations are therefore based on co-solvent systems or aqueoussolvent Systems utilising a water-soluble solvent with one or morewetting agents. Water soluble solvents mix readily with traditionalaqueous adjuvant systems to form combinations of anthelmintics andvaccines. This is not the case with oil based (non-aqueous) systems.

OBJECT

It is an object of the invention to provide an improved injectablecomposition combining a parasitic agent and an antigen or at least onethat provides the public with a useful choice.

STATEMENT OF INVENTION

It has been surprisingly discovered that non-aqueous anthelmintics canbe combined with an antigen using an oil as an adjuvant and carrier togive a stable formulation that can be safely injected into warm bloodedanimals including cattle and sheep.

In one aspect the invention comprises a stable injectable compositioncomprising a non-aqueous parasitic agent in a therapeutically effectamount and an antigen in combination with a liquid carrier that alsoacts as an adjuvant for use with warm blooded animals.

Preferably the non-aqueous parasitic agent is a macrolide compoundselected from group comprising avermectin, ivermectin, doramectin,abamectin, milbemycin and moxidectin, present in from 0.05 to 10% w/v.

More preferably the non-aqueous parasitic agent is chosen from the groupcomprising abamectin, ivermectin, moxidectin and doramectin.

Preferably, the carrier is an oil, either a vegetable oil such as sesameoil, saponine oil, soya bean oil, and corn oil or a mineral adjuvantoil, such as paraffin oil, or purified derivatives of vegetable ormineral oils, such as quiala, which is suitable for injection intoanimals or a mixture thereof. The oil acts as an adjuvant for theimmunising agent and may also act as a solvent for the anthelmintic. Theoil also extends the action of the parasitic agent.

Additionally, the composition may further contain an oil solublesolvent. The oil soluble solvent is chosen from the group comprisingalcohols having four or more carbon atoms for example benzyl alcohol,ethylbenzyl alcohol, phenethyl alcohol and other aromatic monohydricalcohols.

Preferably the alcohol is present in the range from 10-50 w/v %.

The antigen is incorporated into the composition by emulsifying it in asuitable emulsion agent, for example sorbiten oleate (Span 80™ orLiposorb 80™). Other suitable emulsion agents may also be used. Theemulsifier is present in the range of from 5-50 w/v %.

Antigens suitable to be used in the compositions include antigensderived from bacterial and viral pathogens of warm-blooded animals.Preferably the antigen is chosen from the group comprising antigensderived from and toxins of clostridial diseases including Clostridiumsepticum, Clostridium tetani, Clostridium chauvoei, Clostridium novyi,Clostridium sordelli and Clostridium haemolytica. Other possibleantigens include Pasteurella, Pasteurella maltocida and Corynebacteriumpseudotuberculosis and viral antigens for Infectious BovineRhinotracheitis, Bovine Viral Diarrhoea and Parainfluenza.

In another aspect, the invention comprises a method of treatingparasitic diseases and preventing viral and bacterial diseases in warmblooded animals by administration to an animal of a composition asdescribed above.

Preferably the composition is administered to the animal by injectingthe animal.

Preferably the composition is administered at the rate of 0.5-5 mL/50 kgbodyweight of the animal.

PREFERRED EMBODIMENTS

The present invention will be described by way of example only withreference to the following examples.

Formulation 1 (oil based) Part A w/v % Abamectin 1.00 Benzyl Alcohol10.0 Sesame oil 40.0 Paraffin Oil to volume Part B v/v % Part A (1%abamectin) 50.0 mls Span 80 10 gm Vaccine to volume 100% Formulation 2(oil based) Part A w/v % Abamectin (or ivermectin) 1.13 Benzyl Alcohol20.0 Sesame Oil to volume Part B v/v % Part A (1% abamectin) 50.0 mlsSpan 80 10 gm Vaccine to volume 100% Formulation 3 (oil based) Part Aw/v % Ivermectin 1.00 Benzyl Alcohol 10.0 Saponin Oil to volume Part Bv/v % Part A 50.0 mls Span 80 20 gm Vaccine to volume 100% Formulation 4(oil based) Part A w/v % Doramectin 1.13 Benzyl Alcohol 20.0 Sesame Oilto volume Part B v/v % Part A (1% abamectin) 50.0 mls Liposorb 80 10 gmVaccine to volume 100% Formulation 5 (oil based) Part A w/v % Abamectin1.13 Benzyl Alcohol 20.0 Sesame Oil to volume Part B v/v % Part A 50.0ml Sorbitan Oleate 10 gm Antigen 1 4.555 ml Antigen 2 0.135 ml Antigen 30.870 ml Antigen 4 0.933 ml Antigen 5 4.258 ml Benzyl Alcohol to volume100%

Dosage rates for these formulations range from 0.5-5 ml/50 kg bodyweightof the animal.

These preparations have been shown to be stable and do not cause injurywhen injected to warm blooded animals. The parasitic agent and theantigen retain their activity. The formulations have a shelf life ofapproximately two years.

We have found that a formulation of a parasitic agent and an antigen,such as a clostridial antigen, containing an oil such as sesame oil asthe solvent is effective in the treatment of helminthiasis andclostridial diseases in warm blooded animals. Suprisingly, the oil alsoacts as an adjuvant in the composition, enhancing the activity of thevaccine and extending the parasiticide activity of the anthelmintic.Compositions that contained a traditional adjuvant such as alum and theoil stimulated the working of the vaccine to such a level that anadverse reaction was produced in the animal.

Advantages

The compositions of the invention are stable and be stored for longperiods of time without loss of either parasitic agent or antigenpotency.

Industrial Application

The formulations shown above are effective in the treatment of parasiticdiseases and the prevention of bacterial and viral diseases in warmblooded animals, including but not limited to cattle and sheep.

Variations

Although the above examples use abamectin, ivermectin or doramectin, itis possible to use the other anthelmintics of the macrolide group.

Although the use of a clostridial vaccine as the antigen is preferred avariety of other antigens effective against other bacterial or viralpathogens could be incorporated.

Although sesame oil is preferred as the solubilising agent, other oilssuch as soya bean oil, corn oil or mineral adjuvant oils, such asparaffin oils, or suitable mixtures thereof, may be used.

Finally, it will be appreciated a that a variety of other alterationsand modifications may be made to the forgoing without departing from thespirit and scope of the invention.

What is claimed is:
 1. A stable injectable composition suitable for thetreatment of warm-blooded animals consisting essentially of: anon-microencapsulated and non-aqueous macrolide compound present in atherapeutically effective amount, chosen from the macrolide group ofmilbemycins and avermectins compounds; and an antigen in combinationwith a liquid carrier that also acts as an adjuvant for use with thewarm-blooded animals, the carrier including one or more oils selectedfrom the group of vegetable or mineral oils and purified derivativesthereof.
 2. A composition as claimed in claim 1 wherein the non-aqueousmacrolide compound is present in from 0.05-10 w/v %.
 3. A composition asclaimed in claim 1 wherein the non-aqueous macrolide compound is chosenfrom the group comprising abamectin, ivermectin, moxidectin anddoramectin.
 4. A composition as claimed in claim 1 wherein the carrieroil or mixture of oils is suitable for injection into animals and ischosen from the group comprising sesame oil, saponine oil, soya beanoil, corn oil, paraffin oils, purified derivatives of vegetable oils andmineral adjuvant oils and mixtures thereof, and wherein the carrierextends the activity of the parasitic agent.
 5. A composition as claimedin claim 1 further containing an oil soluble solvent chosen from thegroup comprising alcohols having four or more carbon atoms and the oilsoluble solvent is present in a range from 10-50 w/v %.
 6. A compositionas claimed in claim 1 further containing an emulsifier and theemulsifier is present in the range of from 5-50 w/v %.
 7. A compositionas claimed in claim 1 wherein the antigen is chosen from the groupcomprising antigens and toxins for the prevention of clostridialdiseases in warm-blooded animals.
 8. A method of treating parasiticdiseases and treating bacterial and viral diseases in warm bloodedanimals by administration to an animal of a composition consistingessentially of: a non-microencapsulated and non-aqueous macrolidecompound present in a therapeutically effective amount, chosen from themacrolide group of milbemycins and avermectins compounds; and an antigenin combination with a liquid carrier that also acts as an adjuvant foruse with the warm-blooded animals, the carrier including one or moreoils selected from the group of vegetable or mineral oils and purifiedderivatives thereof.
 9. A method as claimed in claim 8 wherein thecomposition is administered to the animal by injecting the animal.
 10. Amethod as claimed in claim 8 wherein the composition is administered atthe rate of 0.5-5 mL/50 kg bodyweight of the animal.